Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor
Chromatin remodeling and gene expression are dynamically controlled by epigenetic regulatory proteins. Histone deacetylases (HDACs) are one class of epigenetic drug targets, with four inhibitors already FDA-approved. HDACs remove the N-ε-acetyl group on lysine side chains of post-translationally modified histones and can be inhibited for controlling aberrant gene expression. Elevated levels of HDAC2 have been found in the brains of Alzheimer’s disease patients and have been associated with a decrease in the genes responsible for learning and memory. Genetic knockdown of HDAC2 in mouse models of the disease reduce the neurodegenerative impairments of memory function.
In this issue, Tamanini et al. (DOI: 10.1021/acsmedchemlett.2c00272) conduct a fragment-based drug
discovery campaign targeting HDAC2
using a combination of crystallography and thermal shift assays. Initial
screening hits identified three potential ligand sites on the protein:
the catalytic zinc group, the entrance tunnel, and the “foot
pocket” at the base of the binding site. Fragment 3 was prioritized, despite having a low ligand efficiency of 0.27,
as it uses an α-amino amide as an under-represented zinc chelating
group, leading to a subtle conformational change opening up larger
region of space in the foot pocket. Structure-guided design using
fragment growing and merging ultimately led to 17 with
sub-micromolar potency, improved ligand efficiency, and good drug-like
properties. Administration of 17 significantly increased
histone acetylation levels of H4K12 in cellular models as well as in vivo. Finally, pharmacokinetic studies demonstrated good
plasma and brain exposure when dosed orally, supporting this lead
as a suitable candidate for further optimization as an Alzheimer’s
therapy.
Highly Potent and Oral Macrocyclic Peptides as a HIV-1 Protease Inhibitor: mRNA Display-Derived Hit-to-Lead Optimization
The human immunodeficiency virus (HIV) leads to chronic autoimmune disease that is currently treated using an anti-retroviral cocktail. HIV therapies inhibit the HIV reverse transcriptase, integrase, protease, and viral fusion mechanisms. Saquinavir and Darunavir/Ritonavir are two FDA-approved HIV-1 protease inhibitor therapies that are limited by metabolic stability, bioavailability, and drug–drug interactions.
To improve upon the currently available HIV protease inhibitors,
Kusumoto et al. (DOI: 10.1021/acsmedchemlett.2c00310) use mRNA display to discover peptide macrocycles with nanomolar
potency, metabolic stability, and oral bioavailability against the
HIV-1 protease. They first identified a 10-residue macrocyclic peptide,
hit molecule 2, with good in vitro activity
but low cell activity. Using structure-based design on a related peptide
with improved cellular activity, they optimized the potency, focusing
on key adjustments of a tryptophan at position 6 and a glycine residue
at position 9, which resulted in a homocyclohexylalanine
and alanine, respectively, in lead molecule 16. A subsequent
α-methyl amino acid scan was employed for improving proteolytic
stability, leading to an α-methyl proline at position 3 in 16. Finally, a penicillamine derivative was substituted
for the macrocyclic linker group for improving metabolic stability.
Through systematic hit-to-lead optimization, peptide macrocycle 16 possessed low nanomolar in vitro and cellular
activity, high metabolic stability, desirable plasma total clearance,
and good oral bioavailability. These studies demonstrate a successful
structure–activity relationship study for optimizing mRNA-derived
peptide macrocycles against an intracellular target. Future lead-to-candidate
optimization will now need to focus on optimizing the solubility and
permeability of these macrocycles.
Triazine-Based Covalent DNA-Encoded Libraries for Discovery of Covalent Inhibitors of Target Proteins
Covalent drugs have long been considered less desirable in most cases, given their potential for irreversible, off-target activity that may lead to side effects. However, following FDA approval of covalent drugs such as Ibrutinib, a chronic lymphocytic leukemia (CLL) and multi-lymphoma treatment, interest has grown in how to build high-value covalent libraries from which candidates can be identified and developed.
In their Letter, Li and co-workers (DOI: 10.1021/acsmedchemlett.2c00127) report a series of new triazine-based covalent DNA-encoded libraries
(DELs) for the discovery of covalent inhibitors of target proteins,
such as Bruton’s tyrosine kinase (BTK), Janus kinase 3 (JAK3),
and peptidyl-prolyl cis/trans isomerase NIMA-interacting-1 (Pin1).
Notably, selected inhibitors from the generated libraries demonstrated
modest to high potency against their respective targets. While DELs
have been popular in the discovery of reversible inhibitors, the use
of DEL affinity selection for screening and identifying irreversible
inhibitors still requires further refinement. Nonetheless, the triazine-based
DEL approach provides a template for further exploration to identify
new selective, covalent inhibitors of target proteins.